Mesenchymal-Stromal Cell-like Melanoma-Associated Fibroblasts Increase IL-10 Production by Macrophages in a Cyclooxygenase/Indoleamine 2,3-Dioxygenase-Dependent Manner

Simple Summary Melanoma is the deadliest form of skin cancer, and the number of newly diagnosed cases is on the rise. In recent years, it has become evident that melanoma-associated fibroblasts (MAFs), which surround the melanoma cells, play a key role in tumor growth and its ability to evade immune attack. We found that MAFs resemble bone marrow mesenchymal stromal cells (MSCs), and on the basis of this, we looked for effects that they might have on macrophages. Like MSCs, MAFs cause macrophages to produce IL-10, an anti-inflammatory agent. IL-10 contributes to cancer growth by suppressing natural anti-cancer immunity and can also interfere with anti-melanoma immunotherapies. Our findings may open new avenues for the development of anti-melanoma treatments based on MAF-macrophage interactions. Melanoma-associated fibroblasts (MAFs) are integral parts of melanoma, providing a protective network for melanoma cells. The phenotypical and functional similarities between MAFs and mesenchymal stromal cells (MSCs) prompted us to investigate if, similarly to MSCs, MAFs are capable of modulating macrophage functions. Using immunohistochemistry, we showed that MAFs and macrophages are in intimate contact within the tumor stroma. We then demonstrated that MAFs indeed are potent inducers of IL-10 production in various macrophage types in vitro, and this process is greatly augmented by the presence of treatment-naive and chemotherapy-treated melanoma cells. MAFs derived from thick melanomas appear to be more immunosuppressive than those cultured from thin melanomas. The IL-10 increasing effect is mediated, at least in part, by cyclooxygenase and indoleamine 2,3-dioxygenase. Our data indicate that MAF-induced IL-10 production in macrophages may contribute to melanoma aggressiveness, and targeting the cyclooxygenase and indoleamine 2,3-dioxygenase pathways may abolish MAF-macrophage interactions.